Type 2 Diabetes Progression

Garry Bieringer was 50 when his doctor told him he had type 2 diabetes. The diagnosis, based on a routine blood test, came as a surprise: Bieringer hadn’t noticed any symptoms. “The doctor just came in and said, ‘I think you have diabetes,’ ” Bieringer recalls.

In the 16 years since, Bieringer’s gone through a process that may be discouragingly familiar to many people with type 2, which affects nearly 28 million Americans. Every few years, his diabetes treatment changes. “It’s my pattern,” he says. “Once I start, after a little while the medication loses effectiveness.”

At first Bieringer took metformin, the drug typically used first to control blood glucose levels in people with type 2 diabetes. After a few years, two more drugs—pioglitazone (Actos) and glyburide (Micronase)—were added to his medication cocktail.

Six years went by, and Bieringer’s doctor recommended a change. The pills that had worked at first were no longer enough to control his blood glucose. Today, he’s no longer on pioglitazone or glyburide. Instead, he takes metformin, injections of a long-acting insulin, fast-acting insulin shots before meals, and a daily shot of exenatide (Byetta), a drug designed to increase his body’s insulin secretion and slow his digestion.

Like many people with type 2 diabetes, Bieringer had a hard time hearing the news that he needed to move from oral medication to shots. “I felt I was failing,” he says. “But my diabetes educator said I wasn’t failing. It was just my body reacting.” Those words of wisdom helped Bieringer come to grips with the steadily increasing demands of his condition.

Chain of Events

For people with type 2, the years after diagnosis almost inevitably bring more intense regimens of oral medication, and sometimes insulin or other injectables as well. “Diabetes is a progressive disease, and often the first agent is not sufficient,” says Kieren Mather, MD, an Indiana University endocrinologist.

Researchers understand the basics of type 2 well. It all comes down to how the body makes and uses insulin, the hormone that tells the body’s cells to absorb glucose from the bloodstream as fuel.

Insulin is produced by beta cells, specialized cells located in the pancreas. When the pancreas can’t produce enough insulin to control blood glucose, diabetes results. “Type 2 diabetes is caused by multiple metabolic defects, but the fundamental problem is the inability of beta cells to make enough insulin for the body’s needs,” says Ravi Retnakaran, MD, an endocrinologist at the Lunenfeld-Tanenbaum Research Institute at Toronto’s Mount Sinai Hospital.

There are two factors at play. First, the body becomes less sensitive to insulin’s commands. That’s what’s called insulin resistance. Second, to get the body’s attention, the “signal” has to get louder—the beta cells in the pancreas have to pump out more insulin, in other words. “What changes is beta cell response,” says Mather. “At first, it improves, to keep things normal in the face of insulin resistance.” If sensitivity to insulin doesn’t improve, the beta cells work harder to produce more insulin.

Unlike people with type 1 diabetes, people with type 2 still have functioning beta cells in the early stages of the disease. Patients usually have no idea their pancreas is struggling to keep up until a doctor flags their blood glucose levels. “People have often had [type 2] diabetes for longer than they realize,” Retnakaran says. “Diabetes is silent.”

Because of their insulin resistance, people in the early phases of type 2 diabetes might even have highly functional beta cells—but not functional enough. “In a person who’s now officially diabetic, beta cell function might be twice what a nondiabetic individual has, but still not sufficient for that person,” Mather says.

As long as there are still functional beta cells, type 2 diabetes can be treated by tackling the body’s insulin resistance. Exercise and weight loss have been shown to make the body more responsive to its own insulin. Metformin works in other ways to keep less of your body’s stored glucose from entering the blood.

But as Bieringer’s experience shows, as time goes on, metformin might not be enough. With insulin resistance still an issue, it’s hard for the pancreas to sustain its above-normal insulin output. “For whatever reason, the function of beta cells worsens over time,” Retnakaran says.

As the beta cells pump out more and more insulin to compensate for the body’s insulin resistance, they sometimes start to falter and fail. “The typical course is that the patient will require more and more antidiabetic medications over time, in the absence of which sugars will rise,” says Retnakaran. “Meanwhile the beta cells are worsening.”

That beta cell failure is responsible for what can feel like an unwinnable race for people with type 2 diabetes. “The overload leads to progressive dysfunction,” Mather says. “It’s like heart disease—the pancreas keeps working too hard and wears out.”

The Theory of Everything

Despite decades of research in thousands of labs around the world, why some people’s beta cells wear out and some don’t is still a mystery. “There’s a change in beta cell function, but we don’t know what makes it so some people can compensate and other people [can’t],” says Mather. “There [are] a lot of ideas, but not a lot of clear evidence.”

One theory is that as the beta cells falter early in type 2, the rising level of glucose in the blood causes a sort of chain reaction. The high glucose is toxic to the beta cells, hastening their failure and death. As they die, blood glucose gets harder to control—and the process speeds up. Research has shown that lowering glucose levels is enough to bring back some beta cell function.

Another possibility is that the immune system is playing a role in beta cell decline. In this scenario, the beta cells might be under attack from the immune system. It’s not unlike what happens in type 1 diabetes, except in the case of type 2, high levels of glucose in the blood might be what sets off the immune reaction. “Perhaps high glucose makes the beta cells poke their heads up above the Whac-a-Mole hole, and now they’re a target,” Mather says. “It may be that there’s a systemic inflammation, and a targeted immune response.”

Genetics could also play a role. Researchers have connected over 70 different genes to type 2 diabetes, though the interplay between them all is nearly impossible to tease apart.

Most frustrating, the answer could be “all of the above.” And it varies from person to person. To slow or halt type 2’s advance, it’s not enough to deal with just the immune system, or obesity. “What makes type 2 diabetes such a difficult problem to solve is that there are so many paths that lead to the same destination,” Mather says. “Maybe we have to block three or four main pathways to have an effect.”

Shifting Into Reverse

Researchers are working to figure out the best way to slow or even change the course of type 2’s progression. There’s lots of evidence, for example, that type 2 diabetes may be reversible. One major clue comes from work with people who have had gastric bypass surgery, a type of bariatric surgery that permanently removes some of the stomach and bypasses some of the small intestine to help patients lose weight.

In 1995, East Carolina University surgeon Walter Pories, MD, published a study showing that a specific type of gastric bypass surgery could reverse type 2 diabetes in 80 percent of patients. People saw their need for insulin injections drop to nothing in a matter of days after the surgery.

Data collected over decades suggested that the remission wasn’t just the result of dramatic weight loss. The surgery does something profound to the patients’ endocrine systems along the way, somehow bringing the pancreas and its failed beta cells back to life.

If they can figure out what’s going on, doctors might be able to replicate the effects of gastric bypass without surgery, slowing or reversing the steady progression of type 2. “There’s something about fuel supply, or hormones, that allows a complete reset and recovery of beta cell function,” says Mather. “It’s a huge clue as to what’s going on, but we don’t have the answer yet.”

A recent American Diabetes Association–funded study led by endocrinologist David Bernlohr, PhD, and surgeon Sayeed Ikramuddin, MD, both at the University of Minnesota–Twin Cities, suggests the remarkable results may have something to do with the parts of the digestive tract bypassed in the surgery, but they’re also pursuing the possibility that calorie restriction plays a role—they just don’t know how yet.

Retnakaran, meanwhile, thinks that some of the factors that lead to type 2 might be reversible using much less dramatic means. He is testing the counterintuitive idea that prescribing insulin injections soon after a type 2 diagnosis—rather than waiting for years until the beta cells have given out—might help slow or even halt the progression of the disease.

To test the theory, Retnakaran is running a series of experiments, working with people recently diagnosed with type 2 to see if giving them insulin soon after diagnosis can “reset” their system. “People are getting insulin early, for a short period of time. A short course, just two to four weeks, addresses this reversible dysfunction and achieves remission of diabetes,” he says.

The idea is that the injected insulin gives the body’s stressed beta cells a break, allowing them to recuperate and recover. And because the beta cells are still functional, they smooth out the ups and downs of insulin injections, reducing the risk of hypoglycemia and the long-term damage caused by high blood glucose. Says Retnakaran: “We’re basically bringing [blood glucose] into the ballpark so beta cells can handle the rest themselves.”

Mather is working on a similar study that starts even earlier, lowering glucose in people with prediabetes to see if they can head off type 2 altogether.

Necessary Upkeep

Past experiments with early insulin therapy have shown that remission isn’t permanent. Three months later, type 2 diabetes is back in a third of patients; a year later, the effects have worn off in more than half. Retnakaran’s hoping to show the technique can still be a useful tool. “We’ve done something good, but the effects are transient,” Retnakaran says. “Maybe we need to treat diabetes very intensely early on, then come back with maintenance.”

Until researchers unravel the secrets of beta cell decline, doctors recommend the time- and lab-tested approach of diet and physical activity to keep the body’s microscopic insulin factories working for as long as possible. “Exercise and weight loss improve beta cell function, improve insulin sensitivity, and delay progression [of type 2 diabetes],” says Mather. “Keeping the load on the beta cells as low as it can be is the best approach.”